Androgen biosynthesis is mainly regulated by the steroid 17(alpha)-hydroxylase/C.sub.17,20 -lyase, which catalyzes the conversion of C.sub.21 steroids precursors (pregnenolone and progesterone) to the related C.sub.19 steroids (androgens) in the testis and adrenal gland. The principal androgen is testosterone. Effective inhibitors of this enzyme would be useful in investigating the physiological role of this enzyme complex and could be useful as a treatment for reducing production of androgens where they have an adverse role in diseases or conditions in vertebrates.
An important utility for such inhibitors may be the treatment of androgen-sensitive prostatic cancer in men. Patients with this disease respond to hormone ablative orchiectomy, but they eventually relapse. However, they may respond to subsequent and different types of hormonal therapy. While orchidectomy eliminates testicular androgens, adrenal androgens may continue to stimulate tumor growth. It is presently unclear whether total ablation of all androgens will be more successful than sequential treatment with different agents. In either case, new types of agents could be of benefit in treating this disease.
Several approaches are presently being used for the treatment of prostatic cancer. These include estrogens, antiandrogens, gonadotropin (LHRH) agonists and enzyme inhibitors.
A number of compounds that inhibit 17(alpha)-hydroxylase/C.sub.17,20, -lyase have been described [1-7], but most of these inhibitors are nonspecific and have low potency. Ketoconazole, an active imidazole fungicide, is currently being studied as a testosterone biosynthesis inhibitor [8,9], and it is used in the treatment of patients with advanced prostatic cancer [10,11]. However, this agent is not highly effective or specific. Also, it reduces cortisol production and has a number of side-effects.
In order to develop new inhibitors of 17(alpha)-hydroxylase/C.sub.17,20 -lyase, especially the C.sub.17,20 -lyase, we synthesized and tested a number of 20-substituted pregnene derivatives, based on the rationale that the modification of substrates at or close to positions which interact with the enzyme active site (i.e., the 20-position for the 17,20-lyase) may result in selective and potent inhibitors for this enzyme.
The 5(alpha)-reduction is a particularly important reaction occurring in the prostate. The enzyme 5(alpha)-reductase regulates the conversion of testosterone to dihydrotestosterone (DHT), which is responsible for the growth of the prostate. Since progesterone is an alternative substrate for the 5(alpha)-reductase, we also evaluated the use of the pregnene derivatives as inhibitors of this enzyme. Inhibition of 5(alpha)-reductase as well as 17(alpha)-hydroxylase/C.sub.17,20 -lyase would block all androgen synthesis, i.e., androstenedione, testosterone and dihydrotestosterone. Such inhibition could be an effective means of treatment for prostatic cancer patients.
Another utilization of these inhibitors might be the treatment of benign prostatic hyperlasia (BPH). Compounds that moderately reduce androgens and estrogens but are potent inhibitors or 5(alpha)-reductase may be effective in BPH, particularly in light of the fact that, in the prostate, DHT is the most active androgen. The known 5(alpha)-reductase inhibitors significantly increase plasma testosterone concentrations above the normal level. Some 20-substituted pregnenes which moderately inhibit the hydroxylase/lyase may serve to maintain normal levels of testosterone while reducing DHT levels.
There is a need to reduce the plasma levels of androgens to effectively treat excess androgens in females and androgen-sensitive cancers in males. In the female, this need can be met by providing compounds that inhibit the hydroxylase/lyase in adrenals and ovaries. In the male, this need can be met by providing compounds that inhibit both enzyme systems, i.e., hydroxylase/lyase in the adrenals and testes, thereby reducing plasma testosterone and androstenedione levels, and 5(alpha)-reductase in the prostate, thereby reducing production of prostatic DHT.
The present invention provides 20-substituted-pregnene derivatives that effectively inhibit both the 17(alpha)-hydroxylase/C.sub.17,20 -lyase and 5(alpha)-reductase enzymes and are therefore useful in reducing the production of androgens where they have an adverse role in a disease or physiological condition in vertebrate species.